Lung cancer, inflammation, and tumor microenvironment
Lung cancer is the leading cause of cancer deaths worldwide. As with all other cancers, untangling the role of systemic inflammation (cancer promoting) versus inflammation in the tumor microenvironment (cancer fighting) is of fundamental clinical importance. A welcome study just published in PLOS One (Public Library of Science) sheds light on this critical conundrum while including the aspect of nutritional status. The authors state:
"The interactions between systemic inflammation and tumoral immune microenvironment are increasingly investigated in cancer patients. Pro-inflammatory cytokines and associated growth factors are involved in carcinogenesis through their effects on tumor cell growth, survival, proliferation and migration. It has been shown that slight elevations of inflammatory markers are associated with an increased risk of non-small cell lung carcinoma (NSCLC) occurrence, and serum C-reactive protein (CRP) has been identified as a prognostic factor in both advanced and resectable NSCLC. The tumoral immune microenvironment has been also shown to be an important determinant of long-term outcome in primary and metastatic tumors: particularly in NSCLC, high levels of mature dendritic cells (mDC) and of CD8+ lymphocytes have been both identified as robust prognostic factors ...Hypothesizing that nutritional status, systemic inflammation and tumoral immune microenvironment play a role as determinants of lung cancer evolution, the purpose of this study was to assess their respective impact on long-term survival in resected non-small cell lung cancers (NSCLC)."
They acquired data for 303 patients surgically treated for NSCLC that included C-reactive protein (CRP) for systemic inflammation, prealbumin levels for nutritional status, and tumoral infiltration by CD8+ lymphocytes and mature dendritic cells in correlation with relevant clinical-pathological parameters. The significance was striking:
"In multivariate analysis, prealbumin levels (Relative Risk (RR): 0.34, CD8+ cell count in tumor tissue (RR = 0.37), and disease stage (RR 1.73 - stage I vs II vs III-IV) were independent prognostic markers. When taken together, parameters related to systemic inflammation, nutrition and tumoral immune microenvironment allowed robust prognostic discrimination; indeed patients with undetectable CRP, high (>285 mg/L) prealbumin levels and high (>96/mm2) CD8+ cell count had a 5-year survival rate of 80% as compared to 18%] in patients with an opposite pattern of values. When stages I-II were considered alone, the prognostic significance of these factors was even more pronounced."
Role of systemic inflammation
Commenting on the crucial role of systemic inflammation the authors note:
"CRP is secreted by hepatocytes following stimulation by circulating pro-inflammatory cytokines, in particular IL-1, TNF-α, and mainly IL-6. Experimental studies have suggested that NSCLC cells are able to release IL-6 and TNF-α. In spite of this, the exact role of systemic inflammation and tumor burden in determining progression and outcome is still controversial. This relationship is even more questionable in “pre-clinical disease”: a study on a large cohort showed that increased CRP levels in cancer-free subjects were associated with a higher risk of lung cancer occurrence. This finding has been recently confirmed by a nested case-control study: among 77 evaluated inflammatory biomarkers, 11 were found to be associated with an increased risk of developing lung cancer, even after adjustment for smoking. Among these 11 markers, CRP was the most robust predictor of lung cancer risk."
Of particular importance for all cancers:
"Moreover, increased baseline CRP levels were associated with early death after diagnosis of any cancer in patients without metastatic disease at diagnosis. These findings strongly suggest a possible role of pre-existing systemic inflammation in determining the occurrence and prognosis of lung cancer...Similarly, systemic inflammation has been reported to be an independent negative prognostic marker in patients with advanced non-small cell lung cancer."
Nutritional status and adequate nutrition
Prealbumin, a plasma protein made by the liver, reflects nutritional status (over a 2 day period) and is valued as a marker for malnutrition. The authors state:
"...we found that CRP levels were strongly and independently correlated (in an inverse manner) with prealbumin levels. Prealbumin levels were in turn correlated with pT parameter, vascular embols, and, as for CRP levels, intra-tumoral density of mDC. Such correlations underline the complex interplay between systemic inflammation, malnutrition, and tumoral immune microenvironment; we may theorize that malnutrition is the first cause of immunodeficiency, and in lung cancer patients this could result in poor infiltration of anti-tumoral immune cells. Therefore, this would explain the strong negative impact of low prealbumin levels on long-term survival. Furthermore, inflammatory status (pre-existent or concomitant with lung cancer) with subsequent increased energy consumption might contribute to malnutrition."
Inflammatory immune response in the tumor microenvironment
In the tumor microenvironment, more inflammation characterized by higher levels of mature dendritic and CD8+ 'killer' cells is favorable:
"...high intra-tumoral densities of mDC and CD8+ T lymphocytes were associated with improved outcome. Interestingly, mDC density in lung cancer reflects the immune response organization within tertiary lymphoid structures (TLS) adjacent to the tumor nests, where CD8+ T cells are supposed to be educated for an efficient antitumor immune response...
And a key point that helps resolve the conundrum of balancing treament of systemic inflammation with the important intra-tumoral inflammatory response:
"In our study, intratumoral mDC density was associated with relevant clinical and biological parameters including not only nutritional ones but also (in an inverse manner) those associated with systemic (CRP levels) and local (smoking, COPD) inflammation...Overall, our results suggest that preexisting systemic inflammation/poor nutritional status could impact the intra-tumoral immune contexture and the patient survival."
In other words, lower systemic inflammation correlated with a better inflammatory response to the tumor. This certainly makes sense considering the pivotal role of systemic inflammation in promoting the development and spread of cancer stem cells, a major determinant of metastasis.
Biomarkers in clinical practice
"Our data show that nutrition, systemic inflammation and tumoral immune contexture are prognostic determinants that, taken together, may predict outcome...The best discrimination was achieved when taking into account simultaneously biomarkers related to inflammation with nutritional status and intra-tumoral immune infiltration. With this model, the differences in survival were remarkable when comparing, in the whole population as in stage I-II disease, patients with high CD8+ T cells density, low CRP levels and high prealbumin levels to those with low CD8+ T cells density, high CRP levels and low prealbumin levels. Interestingly, groups with intermediate biological characteristics had intermediate long-term outcomes."
This speaks volumes for the importance of structuring treatment plans to ensure well-regulated immune function.
IL-10 regulates both systemic and intra-tumoral inflammation
Here we can appreciate a fascinating study published recently in Cancer Immunology Research that demonstrates how the cytokine interleukin-10 (IL-10) both calms systemic inflammation and stimulates anti-tumor immunity:
"Human cancer is characterized by deficits in antigen-specific immunity and intratumoral CD8+ T cells. On the other hand, inflammatory macrophages and mediators of chronic inflammation are highly prevalent in patients with late-stage cancer. Intratumoral T-cell deficiency and chronic inflammation have been linked independently to a poor prognosis in patients with cancer, and therapeutic approaches to overcome either pathology separately are in clinical testing. The anti-inflammatory cytokine interleukin (IL)-10 suppresses macrophage and proinflammatory Th17 T-cell responses by inhibiting the inflammatory cytokines IL-6 and IL-12/23. Corroborating the anti-inflammatory action of IL-10, deficiency in IL-10 leads to a stimulation of inflammatory responses and inflammatory bowel disease."
However, many of us have had a serious concern that IL-10 might suppress the anti-tumor immune response. The authors present data which happily support the opposite conclusion:
"The anti-inflammatory role of IL-10 fostered the assumption that IL-10 undermines the immune response to cancer. However, mice and humans deficient in IL-10 signaling develop tumors spontaneously and at high rates. Overexpression of IL-10 in models of human cancer or treatment with a pegylated IL-10 (PEG-IL-10) led to tumor rejection and long-lasting tumor immunity. IL-10 stimulates cytotoxicity of CD8+ T cells and the expression of IFN-γ in CD8+ T cells. IL-10–induced tumor rejections are dependent on the expression of IFN-γ and granzymes in tumor-resident CD8+ T cells and the upregulation of MHC molecules. These findings reconcile earlier clinical data, which showed that recombinant IL-10 increased IFN-γ and granzymes in the blood of treated individuals. PEG-IL-10 is therefore a unique therapeutic agent, which simultaneously stimulates antitumor immunity and inhibits tumor-associated inflammation."
This is particularly welcome information for clinicians who use low dose cytokine therapy including recombinant IL-10.